Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj; Hideaki Suzuki; Xueqiu  Jian; Chloé Sarnowski; Tavia E Evans; Joshua C. Bis; Gudny Eiriksdottir; Saori  Sakaue; Natalie Terzikhan; Mohamad Habes; Wei Zhao; Nicola J Armstrong; Edith Hofer; Lisa R. Yanek; Saskia Hagenaars; Kumar B Rajan; Erik van den Akker; Rebekah E McWhirter; Stella Trompet; Aniket Mishra; Yasaman Saba; Claudia L Satizabal; Gregory Beaudet; Laurent Petit; Ami Tsuchida; Laura Zago; Sabrina Schilling; Sigurdur Sigurdsson; Rebecca F Gottesman; Cora E Lewis; Neelum T Aggarwal; Oscar L Lopez; Jennifer A. Smith; Maria Valdes Hernandez; Jeroen van der Grond; Margaret J Wright; Maria J. Knol; Marcus Dörr; Russell Thomson; Constance Bordes; Quentin Le Grand; Marie-Gabrielle Duperron; Albert V Smith; David S. Knopman; Pamela J Schreiner; Denis A Evans; Jerome I Rotter; Alexa S Beiser; Susana Muñoz Maniega; Marian Beekman; Julian N. Trollor; David J  Stott; Meike W Vernooij; Katharina Wittfield; Wiro J. Niessen; Aïcha Soumaré; Eric Boerwinkle; Stephen S Sidney; Stephen T Turner; Gail Davies; Anbupalam Thalamuthu; Uwe Völker; Mark A Van Buchem; R Nick Bryan; Josée Dupuis; Mark Bastin; David Ames; Alexander Teumer; Philippe Amouyel; John B J Kwok; Robin Bülow; Ian Deary; Peter R Schofield; Henry Brodaty; Jiyang Jiang; Yasuharu Tabara; Kazuya Setoh; Susumu Miyamoto; Kazumichi Yoshida; Manabu Nagata; Yoichiro Kamatani; Fumihiko Matsuda; Bruce M. Psaty; David A Bennett; Philip L De Jager; Thomas H Mosley; Perminder S Sachdev; Reinhold Schmidt; Helen R. Warren; Evangelos Evangelou; David Alexandre Trégouët; Mohammad A Ikram; Wei Wen; Charles DeCarli; Velandai K Srikanth; J. Wouter Jukema; P Eline Slagboom; Sharon L R Kardia; Yukinori Okada; Bernard Mazoyer; Joanna Wardlaw; Paul A Nyquist; Karen A Mather; Hans J Grabe; Helena Schmidt; Cornelia van Duijn; Vilmundur Gudnason; William T. Longstreth; Launer J Lenore; G Mark Lathrop; Archie Campbell; Sudha Seshadri; Christophe Tzourio; Hieab H H Adams; Paul M Matthews; Myriam Fornage; Stéphanie Debette

doi:10.1038/s41467-020-19111-2

Cerebral small vessel disease genomics and its implications across the lifespan

Muralidharan Sargurupremraj
, Hideaki Suzuki
, Xueqiu Jian
, Chloé Sarnowski
, Tavia E Evans
, Joshua C. Bis
, Gudny Eiriksdottir
, Saori Sakaue
, Natalie Terzikhan
, Mohamad Habes
, Wei Zhao
, Nicola J Armstrong
, Edith Hofer
, Lisa R. Yanek
, Saskia Hagenaars
, Kumar B Rajan
, Erik van den Akker
, Rebekah E McWhirter
, Stella Trompet
, Aniket Mishra

Yasaman Saba, Claudia L Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laura Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F Gottesman, Cora E Lewis, Neelum T Aggarwal, Oscar L Lopez, Jennifer A. Smith, Maria Valdes Hernandez, Jeroen van der Grond, Margaret J Wright, Maria J. Knol, Marcus Dörr, Russell Thomson, Constance Bordes, Quentin Le Grand, Marie-Gabrielle Duperron, Albert V Smith, David S. Knopman, Pamela J Schreiner, Denis A Evans, Jerome I Rotter, Alexa S Beiser, Susana Muñoz Maniega, Marian Beekman, Julian N. Trollor, David J Stott, Meike W Vernooij, Katharina Wittfield, Wiro J. Niessen, Aïcha Soumaré, Eric Boerwinkle, Stephen S Sidney, Stephen T Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A Van Buchem, R Nick Bryan, Josée Dupuis, Mark Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B J Kwok, Robin Bülow, Ian Deary, Peter R Schofield, Henry Brodaty, Jiyang Jiang, Yasuharu Tabara, Kazuya Setoh, Susumu Miyamoto, Kazumichi Yoshida, Manabu Nagata, Yoichiro Kamatani, Fumihiko Matsuda, Bruce M. Psaty, David A Bennett, Philip L De Jager, Thomas H Mosley, Perminder S Sachdev, Reinhold Schmidt, Helen R. Warren, Evangelos Evangelou, David Alexandre Trégouët, Mohammad A Ikram, Wei Wen, Charles DeCarli, Velandai K Srikanth, J. Wouter Jukema, P Eline Slagboom, Sharon L R Kardia, Yukinori Okada, Bernard Mazoyer, Joanna Wardlaw, Paul A Nyquist, Karen A Mather, Hans J Grabe, Helena Schmidt, Cornelia van Duijn, Vilmundur Gudnason, William T. Longstreth, Launer J Lenore, G Mark Lathrop, Archie Campbell, Sudha Seshadri, Christophe Tzourio, Hieab H H Adams, Paul M Matthews, Myriam Fornage, Stéphanie Debette

Research output: Contribution to journal › Article › peer-review

Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral 240 small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 241 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for 242 modification/confounding by hypertension. Aggregated WMH risk variants were associated 243 with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy 244 adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization 245 suggested causal association of increasing WMH-volume with stroke, Alzheimer-type 246 dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in 247 persons without clinical hypertension. Transcriptome-wide colocalization analyses showed 248 association of WMH-volume with expression of 39 genes, of which four encode known drug 249 targets. Finally, we provide insight into BP-independent biological pathways underlying SVD 250 and suggest potential for genetic stratification of high-risk individuals and for genetically-251 informed prioritization of drug targets for prevention trials.

Original language	English
Journal	Nature Communications
Early online date	8 Dec 2020
DOIs	https://doi.org/10.1038/s41467-020-19111-2
Publication status	E-pub ahead of print - 8 Dec 2020

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Sargurupremraj, M., Suzuki, H., Jian, X., Sarnowski, C., Evans, T. E., Bis, J. C., Eiriksdottir, G., Sakaue, S., Terzikhan, N., Habes, M., Zhao, W., Armstrong, N. J., Hofer, E., Yanek, L. R., Hagenaars, S., Rajan, K. B., van den Akker, E., McWhirter, R. E., Trompet, S., ... Debette, S. (2020). Cerebral small vessel disease genomics and its implications across the lifespan. Nature Communications. Advance online publication. https://doi.org/10.1038/s41467-020-19111-2

@article{0be908ace1944a4c9e5df409aa3c443e,

title = "Cerebral small vessel disease genomics and its implications across the lifespan",

abstract = "White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral 240 small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 241 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for 242 modification/confounding by hypertension. Aggregated WMH risk variants were associated 243 with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy 244 adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization 245 suggested causal association of increasing WMH-volume with stroke, Alzheimer-type 246 dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in 247 persons without clinical hypertension. Transcriptome-wide colocalization analyses showed 248 association of WMH-volume with expression of 39 genes, of which four encode known drug 249 targets. Finally, we provide insight into BP-independent biological pathways underlying SVD 250 and suggest potential for genetic stratification of high-risk individuals and for genetically-251 informed prioritization of drug targets for prevention trials.",

author = "Muralidharan Sargurupremraj and Hideaki Suzuki and Xueqiu Jian and Chlo{\'e} Sarnowski and Evans, \{Tavia E\} and Bis, \{Joshua C.\} and Gudny Eiriksdottir and Saori Sakaue and Natalie Terzikhan and Mohamad Habes and Wei Zhao and Armstrong, \{Nicola J\} and Edith Hofer and Yanek, \{Lisa R.\} and Saskia Hagenaars and Rajan, \{Kumar B\} and \{van den Akker\}, Erik and McWhirter, \{Rebekah E\} and Stella Trompet and Aniket Mishra and Yasaman Saba and Satizabal, \{Claudia L\} and Gregory Beaudet and Laurent Petit and Ami Tsuchida and Laura Zago and Sabrina Schilling and Sigurdur Sigurdsson and Gottesman, \{Rebecca F\} and Lewis, \{Cora E\} and Aggarwal, \{Neelum T\} and Lopez, \{Oscar L\} and Smith, \{Jennifer A.\} and \{Valdes Hernandez\}, Maria and \{van der Grond\}, Jeroen and Wright, \{Margaret J\} and Knol, \{Maria J.\} and Marcus D{\"o}rr and Russell Thomson and Constance Bordes and \{Le Grand\}, Quentin and Marie-Gabrielle Duperron and Smith, \{Albert V\} and Knopman, \{David S.\} and Schreiner, \{Pamela J\} and Evans, \{Denis A\} and Rotter, \{Jerome I\} and Beiser, \{Alexa S\} and \{Mu{\~n}oz Maniega\}, Susana and Marian Beekman and Trollor, \{Julian N.\} and Stott, \{David J\} and Vernooij, \{Meike W\} and Katharina Wittfield and Niessen, \{Wiro J.\} and A{\"i}cha Soumar{\'e} and Eric Boerwinkle and Sidney, \{Stephen S\} and Turner, \{Stephen T\} and Gail Davies and Anbupalam Thalamuthu and Uwe V{\"o}lker and \{Van Buchem\}, \{Mark A\} and Bryan, \{R Nick\} and Jos{\'e}e Dupuis and Mark Bastin and David Ames and Alexander Teumer and Philippe Amouyel and Kwok, \{John B J\} and Robin B{\"u}low and Ian Deary and Schofield, \{Peter R\} and Henry Brodaty and Jiyang Jiang and Yasuharu Tabara and Kazuya Setoh and Susumu Miyamoto and Kazumichi Yoshida and Manabu Nagata and Yoichiro Kamatani and Fumihiko Matsuda and Psaty, \{Bruce M.\} and Bennett, \{David A\} and \{De Jager\}, \{Philip L\} and Mosley, \{Thomas H\} and Sachdev, \{Perminder S\} and Reinhold Schmidt and Warren, \{Helen R.\} and Evangelos Evangelou and Tr{\'e}gou{\"e}t, \{David Alexandre\} and Ikram, \{Mohammad A\} and Wei Wen and Charles DeCarli and Srikanth, \{Velandai K\} and \{Wouter Jukema\}, J. and Slagboom, \{P Eline\} and Kardia, \{Sharon L R\} and Yukinori Okada and Bernard Mazoyer and Joanna Wardlaw and Nyquist, \{Paul A\} and Mather, \{Karen A\} and Grabe, \{Hans J\} and Helena Schmidt and \{van Duijn\}, Cornelia and Vilmundur Gudnason and Longstreth, \{William T.\} and Lenore, \{Launer J\} and Lathrop, \{G Mark\} and Archie Campbell and Sudha Seshadri and Christophe Tzourio and Adams, \{Hieab H H\} and Matthews, \{Paul M\} and Myriam Fornage and St{\'e}phanie Debette",

year = "2020",

month = dec,

day = "8",

doi = "10.1038/s41467-020-19111-2",

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Sargurupremraj, M, Suzuki, H, Jian, X, Sarnowski, C, Evans, TE, Bis, JC, Eiriksdottir, G, Sakaue, S, Terzikhan, N, Habes, M, Zhao, W, Armstrong, NJ, Hofer, E, Yanek, LR, Hagenaars, S, Rajan, KB, van den Akker, E, McWhirter, RE, Trompet, S, Mishra, A, Saba, Y, Satizabal, CL, Beaudet, G, Petit, L, Tsuchida, A, Zago, L, Schilling, S, Sigurdsson, S, Gottesman, RF, Lewis, CE, Aggarwal, NT, Lopez, OL, Smith, JA, Valdes Hernandez, M, van der Grond, J, Wright, MJ, Knol, MJ, Dörr, M, Thomson, R, Bordes, C, Le Grand, Q, Duperron, M-G, Smith, AV, Knopman, DS, Schreiner, PJ, Evans, DA, Rotter, JI, Beiser, AS, Muñoz Maniega, S, Beekman, M, Trollor, JN, Stott, DJ, Vernooij, MW, Wittfield, K, Niessen, WJ, Soumaré, A, Boerwinkle, E, Sidney, SS, Turner, ST, Davies, G, Thalamuthu, A, Völker, U, Van Buchem, MA, Bryan, RN, Dupuis, J, Bastin, M, Ames, D, Teumer, A, Amouyel, P, Kwok, JBJ, Bülow, R, Deary, I, Schofield, PR, Brodaty, H, Jiang, J, Tabara, Y, Setoh, K, Miyamoto, S, Yoshida, K, Nagata, M, Kamatani, Y, Matsuda, F, Psaty, BM, Bennett, DA, De Jager, PL, Mosley, TH, Sachdev, PS, Schmidt, R, Warren, HR, Evangelou, E, Trégouët, DA, Ikram, MA, Wen, W, DeCarli, C, Srikanth, VK, Wouter Jukema, J, Slagboom, PE, Kardia, SLR, Okada, Y, Mazoyer, B, Wardlaw, J, Nyquist, PA, Mather, KA, Grabe, HJ, Schmidt, H, van Duijn, C, Gudnason, V, Longstreth, WT, Lenore, LJ, Lathrop, GM, Campbell, A, Seshadri, S, Tzourio, C, Adams, HHH, Matthews, PM, Fornage, M & Debette, S 2020, 'Cerebral small vessel disease genomics and its implications across the lifespan', Nature Communications. https://doi.org/10.1038/s41467-020-19111-2

TY - JOUR

T1 - Cerebral small vessel disease genomics and its implications across the lifespan

AU - Sargurupremraj, Muralidharan

AU - Suzuki, Hideaki

AU - Jian, Xueqiu

AU - Sarnowski, Chloé

AU - Evans, Tavia E

AU - Bis, Joshua C.

AU - Eiriksdottir, Gudny

AU - Sakaue, Saori

AU - Terzikhan, Natalie

AU - Habes, Mohamad

AU - Zhao, Wei

AU - Armstrong, Nicola J

AU - Hofer, Edith

AU - Yanek, Lisa R.

AU - Hagenaars, Saskia

AU - Rajan, Kumar B

AU - van den Akker, Erik

AU - McWhirter, Rebekah E

AU - Trompet, Stella

AU - Mishra, Aniket

AU - Saba, Yasaman

AU - Satizabal, Claudia L

AU - Beaudet, Gregory

AU - Petit, Laurent

AU - Tsuchida, Ami

AU - Zago, Laura

AU - Schilling, Sabrina

AU - Sigurdsson, Sigurdur

AU - Gottesman, Rebecca F

AU - Lewis, Cora E

AU - Aggarwal, Neelum T

AU - Lopez, Oscar L

AU - Smith, Jennifer A.

AU - Valdes Hernandez, Maria

AU - van der Grond, Jeroen

AU - Wright, Margaret J

AU - Knol, Maria J.

AU - Dörr, Marcus

AU - Thomson, Russell

AU - Bordes, Constance

AU - Le Grand, Quentin

AU - Duperron, Marie-Gabrielle

AU - Smith, Albert V

AU - Knopman, David S.

AU - Schreiner, Pamela J

AU - Evans, Denis A

AU - Rotter, Jerome I

AU - Beiser, Alexa S

AU - Muñoz Maniega, Susana

AU - Beekman, Marian

AU - Trollor, Julian N.

AU - Stott, David J

AU - Vernooij, Meike W

AU - Wittfield, Katharina

AU - Niessen, Wiro J.

AU - Soumaré, Aïcha

AU - Boerwinkle, Eric

AU - Sidney, Stephen S

AU - Turner, Stephen T

AU - Davies, Gail

AU - Thalamuthu, Anbupalam

AU - Völker, Uwe

AU - Van Buchem, Mark A

AU - Bryan, R Nick

AU - Dupuis, Josée

AU - Bastin, Mark

AU - Ames, David

AU - Teumer, Alexander

AU - Amouyel, Philippe

AU - Kwok, John B J

AU - Bülow, Robin

AU - Deary, Ian

AU - Schofield, Peter R

AU - Brodaty, Henry

AU - Jiang, Jiyang

AU - Tabara, Yasuharu

AU - Setoh, Kazuya

AU - Miyamoto, Susumu

AU - Yoshida, Kazumichi

AU - Nagata, Manabu

AU - Kamatani, Yoichiro

AU - Matsuda, Fumihiko

AU - Psaty, Bruce M.

AU - Bennett, David A

AU - De Jager, Philip L

AU - Mosley, Thomas H

AU - Sachdev, Perminder S

AU - Schmidt, Reinhold

AU - Warren, Helen R.

AU - Evangelou, Evangelos

AU - Trégouët, David Alexandre

AU - Ikram, Mohammad A

AU - Wen, Wei

AU - DeCarli, Charles

AU - Srikanth, Velandai K

AU - Wouter Jukema, J.

AU - Slagboom, P Eline

AU - Kardia, Sharon L R

AU - Okada, Yukinori

AU - Mazoyer, Bernard

AU - Wardlaw, Joanna

AU - Nyquist, Paul A

AU - Mather, Karen A

AU - Grabe, Hans J

AU - Schmidt, Helena

AU - van Duijn, Cornelia

AU - Gudnason, Vilmundur

AU - Longstreth, William T.

AU - Lenore, Launer J

AU - Lathrop, G Mark

AU - Campbell, Archie

AU - Seshadri, Sudha

AU - Tzourio, Christophe

AU - Adams, Hieab H H

AU - Matthews, Paul M

AU - Fornage, Myriam

AU - Debette, Stéphanie

PY - 2020/12/8

Y1 - 2020/12/8

N2 - White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral 240 small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 241 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for 242 modification/confounding by hypertension. Aggregated WMH risk variants were associated 243 with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy 244 adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization 245 suggested causal association of increasing WMH-volume with stroke, Alzheimer-type 246 dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in 247 persons without clinical hypertension. Transcriptome-wide colocalization analyses showed 248 association of WMH-volume with expression of 39 genes, of which four encode known drug 249 targets. Finally, we provide insight into BP-independent biological pathways underlying SVD 250 and suggest potential for genetic stratification of high-risk individuals and for genetically-251 informed prioritization of drug targets for prevention trials.

AB - White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral 240 small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 241 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for 242 modification/confounding by hypertension. Aggregated WMH risk variants were associated 243 with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy 244 adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization 245 suggested causal association of increasing WMH-volume with stroke, Alzheimer-type 246 dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in 247 persons without clinical hypertension. Transcriptome-wide colocalization analyses showed 248 association of WMH-volume with expression of 39 genes, of which four encode known drug 249 targets. Finally, we provide insight into BP-independent biological pathways underlying SVD 250 and suggest potential for genetic stratification of high-risk individuals and for genetically-251 informed prioritization of drug targets for prevention trials.

UR - https://www.nature.com/ncomms/

U2 - 10.1038/s41467-020-19111-2

DO - 10.1038/s41467-020-19111-2

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

Cerebral small vessel disease genomics and its implications across the lifespan

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